FLT3 (FMS-like tyrosine Kinase 3, also known as Flk2) is a member of the type III receptor tyrosine kinase (RTK) family and plays an important role in the proliferation and differentiation of hematopoietic stem cells. Activating mutation or overexpression of this receptor is found in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis and gastrointestinal stromal tumor (GIST). In addition to activating mutations, autocrine or paracrine ligand stimulation of overexpressed wild type FLT3 can contribute to the malignant phenotype.
The ligand for FLT3 is expressed by the marrow stromal cells and other cells and synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells. FLT3 has been implicated in hematopoietic disorders which are pre-malignant disorders including myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), angiogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (IMF), and polycythemia vera (PV), the cytopenias, and pre-malignant myelodysplastic syndromes. Hematological malignancies include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), multiple myeloma, (MM) and myeloid sarcoma. Aberrant expression of FLT3 has been documented in both adult and childhood leukemias including acute myeloid leukemia (AML), AML with trilineage myelodysplasia (AML/TMDS), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS).
The FLT3 receptor is also expressed in a large portion of dendritic cell progenitors, and stimulation of the receptor causes the proliferation and differentiation of these progenitors into dendritic cells (DC). Since dendritic cells are the main initiators of the T-cell mediated immune response, including the autoreactive immune response, FLT3 inhibition is a mechanism for down-regulating DC-mediated inflammatory and autoimmune responses. One study shows the FLT3 inhibitor CEP-701 to be effective in reducing myelin loss in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. A high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (Rolland et al., J. Immunol., 2005, 174:3067-3071).
The proto-oncogene receptor tyrosine kinase (RTK) MER (also known as MERTK, Nyk, and Tyro12) is a member of the MER/AXL/TYRO3 receptor kinase family. Within the hematopoietic lineages, MER is expressed in dendritic cells, monocytes/macrophages, NK cells, NKT cells, megakaryocytes, and platelets. However, MER is not expressed in normal lymphocytes. In studies of T-cell ALL, it was demonstrated that ectopic expression of MER contributes to the development of lymphoblastic leukemia and lymphoma. MER RNA expression has also been demonstrated in E2A-PBX1+B-ALL. MER is known to activate anti-apoptotic signaling proteins, including Akt and Erk 1/2. Furthermore, a recent microarray study identified gash, a ligand for MER, as a gene which promotes survival of HEK-293 cells under conditions of serum withdrawal. Ectopic expression of MER was found in pediatric B-cell ALL Inhibition of MER prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, it was discovered cross-talk between the MER and mammalian target of rapamycin (mTOR) signaling pathways. MER is recently paid attention as a novel therapeutic target in ALL (Linger et al., Blood, 2009, 114(13):2678-87). Abnormal expression and activation of MER provide a survival advantage for leukemia cells. Furthermore, inhibition of MER may enhance the sensitivity of leukemia cells to cytotoxic agents.
VEGFR3 (vascular endothelial growth factor receptor 3, also known as FLT4, PCL) is a tyrosine kinase receptor of VEGFR 1, 2, 3 family for vascular endothelial growth factors (VEGF) C and D and plays an important role in lymphangiogenesis and maintenance of the lymphatic endothelium. VEGF is a signaling protein involved in the regulation of angiogenesis and vasculogenesis. It is also known that the VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumors. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, it was found that the activated VEGF-C/VEGFR-3 axis enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis in several types of solid tumors such as gastric cancer, breast cancer, non-small cell lung cancer, cervical cancer, colorectal cancer, prostate cancer, Kaposi sarcoma, head and neck squamous cell carcinoma, endometrial carcinoma and mesothelioma (Su et al., Br. J. Cancer. 2007 96(4):541-5)
Aurora-B (also known as serine/threonine kinase 12 and ARK2), one of Aurora family A, B, C, is a intracellular serine/threonine kinase, which is known to be directly involved in regulating the cleavage of polar spindle microtubules and is a key regulator for the onset of cytokinesis during mitosis. An important target of Aurora B is histone H3, which is a critical regulator of chromosome condensation. Aurora kinases have been strongly linked to the progression of human cancers. Overexpression of Aurora A and B is observed in many cancers such as prostate, colon, pancreas, breast and thyroid cancers. It was also found that hematologic malignant cells including those from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) aberrantly expressed Aurora A and B kinases (Ikezoe et al., Blood, 2006, 108:563a).
Protein kinases are attractive and proven targets for new therapeutic agents to treat a range of human diseases, with examples including Gleevec and Tarceva. The FLT-3, MER, VEGFR and Aurora-B kinase are especially attractive due to their association with numerous human cancers, particularly leukemia and lymphoma, and their roles of playing in the proliferation of these cancer cells.
WO2011053861 discloses kinase inhibitors which show inhibitory activity against multiple kinases including but not limited to FLT3 (FMS-like tyrosine Kinase).
Therefore, there remains a need to identify further compounds which have potent activity against FLT3 enzymes, higher selectivity to other kinases, and good pharmacokinetic profile to be useful to treat the FLT3 related diseases.